The high contrast for breast pathology afforded by electromagnetic (EM) properties in the 300-3000 MHz range more than motivates the development of imaging technologies that seek to exploit these differences with normal tissue. Indeed, tomographic methods are attractive in this context because they generate spatial maps of imaged parameters in order to localize disease. Project III, Microwave Imaging and Spectroscopy (MIS), targets the development and evaluation of broadband, multi-spectral microwave tomography for breast imaging applications. During the current funding period, Project III has successfully deployed a clinical imaging system which transceives propagating EM fields through a non-contacting antenna array under computer-controlled axial translation to deliver comfortable exams to the pendant breast immersed in a fluid used to promote signal coupling into the region of interest. This system has been involved in more than 100 clinical sessions which have (i) determined that EM breast properties are higher and more heterogeneous than expected, (ii) begun to establish the normal breast response showing statistically significant increases in property values with increasing breast radiodensity, and (iii) suggested that there is sufficient property contrast to detect screening abnormalities. These encouraging developments and early clinical results motivate a new set of technical and clinical goals for the next funding period that center on three primary areas of investigation: (a) to develop and evaluate 3D microwave imaging, (b) to understand the impact of breast tissue composition on the images produced and (c) to validate resultant images through clinical studies organized by the Clinical Core. More specifically, the Project III aims for the proposed funding period are (1) to develop 3D imaging through faster, more accurate data acquisition and concomitant software advances to exploit anatomical priors through coregistration, high frequencies and multi-spectral methods, (2) to develop, validate and utilize a probe-based measurement system for local property studies at the time of surgery but prior to histopathology on breast tissues previously imaged in vivo, (3) to validate the new system advances in phantoms and clinical cases correlated with MR (Magnetic Resonance) and (4) to continue clinical studies in.collaboration with the Clinical Core which target screening abnormalities recommended for biopsy, palpable masses on clinical breast exams and locally-advanced cancers receiving neoadjuvant therapy. If successful, it is expected that these aims will generate sufficient evidence to allow convincing estimates of the potential of MIS as an alternative for differential diagnosis, and pilot data in support of a role in treatment prognosis and therapy monitoring which would inform decisions on initiation of multi-center trials with MIS technology in the future.